This research is closely related to NIMH Research Topic #93 (C.3) in the SBIR Grant Solicitation. Recombinant adeno-associated viral (rAAV) vectors are to be developed for transgene delivery to the central nervous system (CNS). In particular, we are engineering rAAVs designed to transduce an expression cassette carrying the human gene for glial cell-derived neurotrophic factor (GDNF). GDNF is a novel member of the transforming growth factor-beta (TGF-beta) superfamily which displays potent trophic effects on dopamine neurons. Dopaminergic function plays a key role in affective and regulatory behaviors and in human neuropsychiatric and neurodegenerative diseases. A number of disorders, such as schizophrenia, attention deficit/hyperactivity disorder, and Parkinson's disease, involve some dysfunction in dopaminergic pathways. Gene therapy employing rAAVs may provide a means of directly altering the physiology and gene expression of the affected cells within the CNS. PROPOSED COMMERCIAL APPLICATION: A substantial fraction of the U.S. population is affected by neuropsychiatric and neurodegerative disorders involving misregulation or breakdown of dopaminergic pathways. Diseases such as schizophrenia, attention deficit/hyperactivity disorder, and Parkinson's disease cost our health care systems billions of dollars each year, and yet in most cases the currently available medications fail to successfully treat these disorders. Gene therapy promises to revolutionize the treatment of such disease.